Hallmarks of aging that negatively impact health include weight gain and reduced physical fitness, which can increase insulin resistance and risk for many diseases including type 2 diabetes. The underlying mechanism(s) for these phenomena is poorly understood. Aging increases oxidative stress and DNA breaks and activates DNA-dependent protein kinase (DNA-PK) in skeletal muscle, which suppresses mitochondrial function, energy metabolism and physical fitness. We find that endonuclease G (EndoG), a mitochondrial nuclease, regulates DNA-PK in response to oxidative stress. Deficiency of EndoG increases DNA-PK activity at low levels of oxidative stress, but decreases DNA-PK at high levels of oxidative stress. This observation links DNA-PK activity to mitochondrial function, and we are in the process of elucidating the molecular mechanism for this link. We also examined the role of PDE4D in the weight changes associated with aging. We discovered that PDE4D inhibitor reduces body weight and fat content in old mice.